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and Asthma Medical Group and Research Center, San Diego, California
Colorado Allergy & Asthma Centers, Denver, Colorado
z
AstraZeneca, Mlndal, Sweden
x
T-STAT, LLC Statistical Consulting and Contracting, Downingtown, Pennsylvania
k
AstraZeneca LP, Wilmington, Delaware
y
A R T I C L E
I N F O
Article history:
Received for publication May 11, 2015.
Received in revised form August 24, 2015.
Accepted for publication September 11,
2015.
A B S T R A C T
Background: Budesonide is approved for delivery using a nebulized solution and dry-powder inhaler, but its
use through a pressurized metered-dose inhaler (pMDI) in pediatric patients with asthma has not been
determined.
Objective: To examine the efcacy and safety of 160 mg twice daily of budesonide through a pMDI vs placebo
in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.
Methods: A 6-week, international, multicenter, double-blinded, parallel-group, phase 2 study randomized
304 pediatric patients (mean age, 9 years; 21.7% <8 years) 1:1 to 160 mg (80 mg 2 inhalations) twice daily of
budesonide through a pMDI or placebo after a 7- to 21-day run-in period. The primary efcacy end point was
change from baseline in morning peak expiratory ow (PEF); safety end points included adverse events, vital
signs, and discontinuations.
Results: Budesonide treatment signicantly improved morning PEF vs placebo; mean treatment effect
(budesonide vs placebo) was 13.6 L/min (P < .0001). Budesonide also showed signicant improvements vs
placebo for forced expiratory volume in 1 second, evening PEF, forced expiratory ow at 25% to 75% of
pulmonary volume, reliever medication use, nighttime awakenings, awakenings with reliever use, and
percentage of patients with at least 15- and at least 30-L/min increase in morning PEF from baseline. The
numbers of patients experiencing adverse events and discontinuations were smaller in the budesonide than
in the placebo group. No serious adverse events were reported.
Conclusion: Budesonide at 160 mg twice daily through a pMDI was generally well tolerated and signicantly
improved lung function, symptoms, rescue medication use, and nighttime awakenings vs placebo in children
6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.
2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Inhaled corticosteroids (ICSs) are the most consistently effective
long-term asthma-control medication and are recommended as
rst-line treatment for pediatric patients with asthma.1,2 The National Asthma Education and Prevention Program Expert Panel
Report 3 recommends ICSs as the preferred therapy to initiate longterm asthma-control treatment for children of all ages.1 The
Reprints: Eli O. Meltzer, MD, Allergy and Asthma Medical Group and Research
Center, 5776 Rufn Road, San Diego, CA 92123; E-mail: eliomeltzer@gmail.com.
Disclosures: Authors have nothing to disclose.
Funding Sources: This study was supported by AstraZeneca LP (Wilmington,
Delaware). Medical writing assistance was provided by Scientic Connexions
(Lyndhurst, New Jersey) and funded by AstraZeneca LP.
Trial Registration: Clinicaltrials.gov, identier NCT01136382.
http://dx.doi.org/10.1016/j.anai.2015.09.007
1081-1206/ 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
E.O. Meltzer et al. / Ann Allergy Asthma Immunol 115 (2015) 516e522
517
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E.O. Meltzer et al. / Ann Allergy Asthma Immunol 115 (2015) 516e522
Figure 1. (A) Study design and (B) patient disposition. aTwo patients in the placebo group had predened asthma events, but their primary reason for withdrawal was given as
other. bid, twice daily; pMDI, pressurized metered-dose inhaler.
E.O. Meltzer et al. / Ann Allergy Asthma Immunol 115 (2015) 516e522
519
Table 1
Demographics of all randomized patients
Demographic characteristics
Placebo pMDI
bid (n 152)
9 (1.6)
9 (1.6)
33 (21.7)
119 (78.3)
33 (21.7)
119 (78.3)
98 (64.5)
54 (35.5)
94 (61.8)
58 (38.2)
132
13
1
6
(86.8)
(8.6)
(0.7)
(3.9)
138 (90.8)
7 (4.6)
0
7 (4.6)
Baseline demographic characteristics were similar between treatment groups. No asthma medications other than short-acting bagonists were taken by any patient during the run-in period. More
budesonide-treated (n 121; 79.6%) than placebo-treated (n 92;
60.5%) patients completed the study (Fig 1B).
Patients
Efcacy
Primary variable
Greater improvement in morning predose PEF was observed for
budesonide-treated vs placebo-treated patients (least-squares [LS]
mean change from baseline to treatment period average of 17.8 vs
4.1 L/min, respectively), with an average treatment effect (budesonide vs placebo) of 13.6 L/min (P < .0001) during the study
period. Improvements began at week 1, continued through week 3,
and were maintained thereafter for the duration of the 6-week
treatment period (Fig 2). Sensitivity analysis of the improvement
in morning predose PEF showed no qualitative difference by
country, region, or age group.
Post hoc PEF responder analysis
The percentage of patients who met the response criterion of an
improvement of at least 15 L/min in predose morning PEF was
signicantly larger in the budesonide group than in the placebo
group beginning at week 1 (38.7% vs 20.5%; P < .001) and
continuing through the 6-week treatment period (week 2 [50.3% vs
Figure 2. Mean change from baseline in morning PEF. Data points are means of
patients weekly mean change from baseline (including last observation carried
forward). Baseline is the mean of the last 7 available days of the run-in period.
Treatment period averages (excluding last observation carried forward values) are
plotted at the end for each treatment group. bid, twice daily; PEF, peak expiratory
ow; pMDI, pressurized metered-dose inhaler.
520
E.O. Meltzer et al. / Ann Allergy Asthma Immunol 115 (2015) 516e522
29.1%; P < .001], week 3 [53.6% vs 31.1%; P < .0001], week 4 [55.0%
vs 34.4%; P < .001], week 5 [51.0% vs 33.8%; P .0025], and week 6
[52.9% vs 36.4%; P .0039]; Fig 3A).
When the morning predose PEF response criterion was
increased to at least 30-L/min improvement, the percentage of
patients who met the responder criteria was signicantly larger in
the budesonide group than in the placebo group at week 2 (31.8% vs
11.3%; P <.0001), week 3 (29.8% vs 17.2%; P .01), week 4 (33.1% vs
20.5%; P .014), week 5 (32.5% vs 19.9%; P .013), and week 6
(34.4% vs 21.9%; P .015) but not at week 1 (16.7% vs 10.0%; P
.086; Fig 3B).
Secondary variables
Treatment with budesonide resulted in signicantly greater
improvements from baseline in morning predose FEV1 vs those
with placebo (LS mean change from baseline to treatment period
average of 0.00 vs 0.06 L, respectively), with a treatment effect of
0.06 L in favor of budesonide (P .0047). The improvement in
morning predose FEV1 began in the rst week of treatment and was
maintained throughout the rest of the treatment period (Fig 4). In
contrast, placebo-treated patients showed a decrease in morning
predose FEV1 after week 1, which continued to decrease
throughout the rest of the treatment period (Fig 4).
Budesonide-treated patients had a LS mean improvement of
0.04 L over placebo for mean FVC, but this difference was not statistically signicant (Table 2). Mean baseline FEF25e75 was signicantly improved with budesonide treatment from baseline to
treatment period average vs placebo (Table 2). Statistically signicant improvement in evening PEF mean change from baseline to
Figure 4. Mean change from baseline for in-clinic morning predose FEV1. Data
points are means of the individual patient FEV1 change from baseline (including last
observation carried forward values) at that visit. Baseline is dened as the latest
non-missing assessment before the rst dose (typically, visit 3 [randomization]).
Treatment period averages (excluding last observation carried forward values) also
are plotted at the end for each treatment group. bid, twice daily; FEV1, forced
expiratory volume in 1 second; pMDI, pressurized metered-dose inhaler.
Figure 3. Percentage of patients with improvements of (A) at least 15 L/min and (B)
at least 30 L/min in morning peak expiratory ow. Data points are percentages of
patients with mean change from baseline (including last observation carried forward) of at least 15 and at least 30 L/min. Baseline is the mean of the last 7 available
days of the run-in period. *P < .05 for budesonide vs placebo. bid, twice daily; pMDI,
pressurized metered-dose inhaler.
E.O. Meltzer et al. / Ann Allergy Asthma Immunol 115 (2015) 516e522
521
Table 2
Treatment effect for other secondary outcomes
Change from baseline to treatment period averagea
Treatment effectb
(budesonide vs placebo)
P valuec
FVC (L)d
FEF25e75 (L/s)d
Evening PEF (L/min)e
Daytime asthma symptom scoree
Nighttime asthma symptom scoree
Nighttime awakenings due to asthma symptoms (%)e
Nighttime awakenings with reliever medication use (%)e
Total rescue medication use (inh/d)d
Daytime rescue medication use (inh/d)d
Nighttime rescue medication use (inh/d)d
2.18
1.55
217.2
1.3
1.1
23.3
12.4
1.3
0.8
0.6
2.18
1.59
221.0
1.3
1.2
20.7
14.0
1.4
0.8
0.6
0.04
0.10
10.8
0.2
0.1
4.7
3.9
0.5
0.3
0.2
.0673
.0216
.0004
.0004
.0079
.0095
.0007
<.0001
.0001
<.0001
Abbreviations: bid, twice daily; FEF25e75, forced midexpiratory ow between 25% and 75% of forced vital capacity; FVC, forced vital capacity; inh/d, inhalations per day; PEF,
peak expiratory ow; pMDI, pressurized metered-dose inhaler.
Treatment period average is dened as the mean value across all available on-treatment visits. Change from baseline to the end point was analyzed using an analysis of
covariance model with terms for treatment, age group (<8 and 8 years of age), and country, with baseline as a covariate.
b
Least-squares mean treatment difference (budesonide vs placebo).
c
Baseline is dened as the latest non-missing assessment before the rst dose (typically visit 3, randomization).
d
Baseline is dened as the mean of the last 7 available days of the run-in period.
e
Baseline is dened as the percentage of days on which a patient experienced nighttime awakenings out of the available days on which data were collected during the last 7
days of the run-in period.
a
Table 3
Most common adverse eventsa (frequency 2%)
Figure 5. Time to withdrawal owing to an asthma-related event. Time to withdrawal from the study was dened as the time (days) from the date of the rst dose
at randomization to the date of withdrawal. For patients who completed the study,
time to withdrawal was censored at the day of study completion. The symbols on
each line indicate those censored patients. A fraction of patients from each treatment group continued beyond the nominal end of the study (42 days), without
withdrawing because of a predened asthma event. Each symbol beyond 42 days
notes the day that a patient stopped treatment. Only 1 patient in each treatment
group remained in the study beyond 49 days and 0 beyond 56 days. bid, twice daily;
pMDI, pressurized metered-dose inhaler.
Adverse event
Budesonide pMDI
160 mg bid (n 152)
Placebo pMDI
bid (n 152)
44
12
5
1
3
4
3
1
1
0
62
9
8
11
8
4
4
3
3
3
(28.9)
(7.9)
(3.3)
(0.7)
(2.0)
(2.6)
(2.0)
(0.7)
(0.7)
(40.8)
(5.9)
(5.3)
(7.2)
(5.3)
(2.6)
(2.6)
(2.0)
(2.0)
(2.0)
522
E.O. Meltzer et al. / Ann Allergy Asthma Immunol 115 (2015) 516e522
patients at week 1 and >50% throughout the study for the 15-L/min
criterion) and sustained throughout the treatment period, further
supporting the efcacy benets of budesonide over placebo.
However, it is important to note that this study was designed for
patients who required a low-dose ICS with a relatively mild impact
of asthma; therefore, the 15-L/min criterion is appropriate for this
population with mild asthma; future studies are required to evaluate appropriate response criteria in pediatric patients with more
severe asthma.
As a group, the change in PEF and other secondary outcome
measurements occurred rapidly in response to budesonide treatment (by weeks 1e3) and were maintained throughout the rest of
the treatment period. However, in the placebo group, morning PEF
remained at and morning predose FEV1 decreased after week 1 of
treatment. These data in the placebo group conrm that this patient population did require ICS therapy, because they began to
experience a more signicant impact of asthma on lung function
when left untreated. Future studies of longer duration including
pediatric patients with asthma of different severities are needed to
evaluate whether this rapid response to budesonide treatment has
predictability for a patients long-term response to treatment and
whether it is consistent across different patients.
Results of safety analyses did not show any concerns for the
doses tested, and no serious AEs were reported. Importantly, the
safety prole was similar to the known safety prole of budesonide
in other formulations and devices when studied in children 6 to
younger than 12 years.3,4,12 As in the present study, common AEs
reported in studies with budesonide administered by dry-powder
inhaler and nebulizer were respiratory infections (eg, sinusitis,
rhinitis, pharyngitis).4,12 Although 5 serious AEs were reported
across all groups in a study by Shapiro et al,4 including 2 asthma
exacerbations, none were judged to be causally related to the study
drug. In the ndings of all studies, the incidence of AEs for budesonide was similar to that for placebo.3,4,12 Together, the efcacy
and safety data support the administration of a suspension
formulation of 160 mg bid of budesonide administered through a
pMDI in children with asthma 6 to younger than 12 years.
Currently, budesonide is approved in the United States for use as
maintenance treatment for asthma once or twice daily as a suspension from a nebulizer in children 12 months to 8 years old13 and
twice daily as an inhalation powder through a dry-powder inhaler
in children 6 to 17 years old.14 Budesonide delivered through a
pMDI would allow the introduction of another device option for
this age group, because differences in attributes, such as metering,
means of dispersion, type of formulation, and design, can make one
device more preferred by or suitable for some patients than
others.15,16
Ultimately, the health care professional will select the device
that best meets the individual patients needs and with which the
patient is satised and comfortable.15 For these reasons, it is
benecial to show the efcacy and safety of asthma medications
Acknowledgement
The authors thank Scientic Connexions (Lyndhurst, New Jersey)
for providing medical writing support funded by AstraZeneca LP
(Wilmington, Delaware).
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